9UWM

A combined cryo_EM structure of Cagrilintide-CTR-Gs complex

Summary for 9UWM

• Entry DOI: 10.2210/pdb9uwm/pdb
• EMDB information: 64560
• Descriptor: Guanine nucleotide-binding protein g(s) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Cagrilintide, ... (5 entities in total)
• Functional Keywords: gpcr, ctr, membrane protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 5
• Total formula weight: 145950.32

Authors

Zhao, L.,Gu, Y.,Yuan, Q. (deposition date: 2025-05-12, release date: 2026-05-27)

Primary citation

Gu, Y.M.,Yuan, Q.N.,Li, X.,He, Q.,Xu, H.E.,Zhao, L.H.
Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors.
Acta Pharmacol.Sin., 47:162-172, 2026

PubMed Abstract: The global obesity epidemic and its associated metabolic disorders urgently require more effective therapeutic interventions, particularly multi-pathway targeting therapies. Cagrilintide (Cagri), functioning as a dual amylin receptor (AMYRs) and calcitonin receptor (CTR) agonist (DACRA), demonstrates significant efficacy in obesity treatment, although its structural activation mechanism remains unclear. This study elucidates the non-selective activation mechanism by determining cryo-EM structures of Cagri bound to AMYR-G and CTR-G complexes. Cagri adopts similar "bypass" binding modes in both receptors, which is distinct from other existing DACRAs that primarily achieve extended half-life through N-terminal lipid modification. Key molecular features include the F23 residue anchoring the peptide at the receptor transmembrane (TM) bundle level and the micelle, an E14-R17 intramolecular salt bridge enhancing helical stability, and C-terminal P37 interaction with the receptor ECD. These features collectively enable non-specific binding and activation across different receptors. Both structural and functional analyses revealed Cagri's non-selective activation of G signaling pathways through CTR and AMYR. These findings provide a comprehensive structural framework for developing next-generation anti-obesity drugs based on dual receptor activation mechanisms.

PubMed: 40847076
DOI: 10.1038/s41401-025-01635-2

Experimental method

ELECTRON MICROSCOPY (3.1 Å)